title: Improving outcomes for high-risk ALL: translating new discoveries into clinical care.
abstract: High-risk (HR) acute lymphoblastic leukemia (ALL) remains one of the greatest challenges in pediatric oncology. Relapsed ALL is a leading cause of death in young people, and further improvements in outcome will required the development of therapeutic approaches directed against rational therapeutic targets, as escalation of the intensity of existing therapies is limited by toxicity. This review summarizes advances in the biology and treatment of HR and relapsed ALL presented at a symposium at the 2010 American Society for Pediatric Hematology and Oncology Annual Meeting. Analysis of large patient cohorts has identified several factors associated with HR of relapse including older age, T-lineage disease, and persisting minimal residual disease (MRD) early in therapy. As the results of salvage therapy remain poor, new treatment approaches are needed. BCR-ABL1-positive (Ph+) ALL has historically had a very poor outcome, but recent studies have demonstrated the impressive improvements in treatment outcome with the use of tyrosine kinase inhibitors (TKIs). High-resolution genomic profiling of genetic alterations and gene expression has revolutionized our understanding of the genetic basis of ALL, and has identified several alterations associated with poor outcome, including mutations of the lymphoid transcription factor gene IKZF1 (IKAROS), activating mutations of Janus kinases, and rearrangement of the lymphoid cytokine receptor gene CRLF2. These data indicated that the genetic basis of HR-ALL is multifactorial, and have also provided a new potential therapeutic option directed at JAK inhibition.
authors.affiliation: Center for Cancer and Blood Disorders, The Children's Hospital and Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
mesh_terms: D002648:Child; D002869:Chromosome Aberrations; D003398:Craniosynostoses; D018572:Disease-Free Survival; D016142:Holoprosencephaly; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D012008:Recurrence; D012307:Risk Factors; D015996:Survival Rate; D017211:Treatment Failure; D016896:Treatment Outcome